Trial Outcomes & Findings for Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight (NCT NCT00734539)

Last Updated: 2019-03-01

Results Overview

The primary endpoint for the study is death or candidiasis. 1. Death prior to study day 49. 2. Candidiasis prior to study day 49 1. Definite: isolation of Candida from normally sterile body fluid (blood, CSF, urine \[obtained via sterile catheterization or suprapubic tap\], peritoneal fluid). 2. Probable: i. \> 5 days of consecutive antifungal therapy AND both: ii. Thrombocytopenia \<150,000/mm3 iii. Positive Candida culture from nonsterile site (ETS, bag urine)

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

362 participants

Primary outcome timeframe

study day 49

Results posted on

2019-03-01

Participant Flow

Participant milestones

Participant milestones
Measure	Fluconazole fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Main Study STARTED	189	173
Main Study COMPLETED	152	138
Main Study NOT COMPLETED	37	35
Long Term Follow up STARTED	152	138
Long Term Follow up COMPLETED	118	107
Long Term Follow up NOT COMPLETED	34	31

Reasons for withdrawal

Reasons for withdrawal
Measure	Fluconazole fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Main Study Death	33	32
Main Study Physician Decision	2	0
Main Study Withdrawal by Subject	1	3
Main Study Enrolled in error; ineligible	1	0

Baseline Characteristics

Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses	Total n=361 Participants Total of all reporting groups
Age, Continuous	3 days n=5 Participants	3 days n=7 Participants	3 days n=5 Participants
Sex: Female, Male Female	109 Participants n=5 Participants	98 Participants n=7 Participants	207 Participants n=5 Participants
Sex: Female, Male Male	79 Participants n=5 Participants	75 Participants n=7 Participants	154 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	21 Participants n=5 Participants	25 Participants n=7 Participants	46 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	167 Participants n=5 Participants	148 Participants n=7 Participants	315 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	102 Participants n=5 Participants	94 Participants n=7 Participants	196 Participants n=5 Participants
Race (NIH/OMB) White	73 Participants n=5 Participants	70 Participants n=7 Participants	143 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
birth weight	653 grams n=5 Participants	640 grams n=7 Participants	650 grams n=5 Participants
Gestational Age at Birth	25 weeks n=5 Participants	25 weeks n=7 Participants	25 weeks n=5 Participants

PRIMARY outcome

Timeframe: study day 49

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Death or Candidiasis	31 participants	37 participants

SECONDARY outcome

Timeframe: 18-22 months corrected gestational age

Population: Attended the follow-up visit and had complete data on composite endpoint

Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy

Outcome measures

Outcome measures
Measure	Fluconazole n=87 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=84 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Neurodevelopmental Impairment	27 participants	23 participants

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Definite or probable

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Candidiasis	8 participants	19 participants

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Stage II or Higher Necrotizing Enterocolitis	25 participants	23 participants

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Focal Intestinal Perforation	16 participants	9 participants

SECONDARY outcome

Timeframe: 36 weeks corrected gestational age

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Chronic Lung Disease	114 participants	93 participants

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Patent Ductus Arterious Requiring Surgical Ligation	46 participants	43 participants

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Periventricular Leukomalacia	10 participants	6 participants

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Retinopathy of Prematurity Requiring Laser Surgery	29 participants	25 participants

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Length of Hospitalization	113 days Interval 90.0 to 148.0	107 days Interval 88.0 to 128.0

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Positive Bacterial Infection From a Sterile Site	109 participants	100 participants

SECONDARY outcome

Timeframe: prior to hospital discharge, up to 15 ½ months

Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.

Grade 3 or 4

Outcome measures

Outcome measures
Measure	Fluconazole n=188 Participants fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 Participants Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Intraventricular Hemorrhage	33 participants	31 participants

Adverse Events

Fluconazole

Serious events: 83 serious events

Other events: 1 other events

Deaths: 0 deaths

Placebo

Serious events: 68 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Fluconazole n=188 participants at risk fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 participants at risk Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Hepatobiliary disorders Hyperbilirubinaemia Neonatal	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • Number of events 1 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Investigations Gamma-Glutamyltransferase Increased	0.53% 1/188 • Number of events 1 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks

Additional Information

Daniel K. Benjamin Jr

Duke Univiersity Medical Center

Phone: 919-668-7081

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Fluconazole n=188 participants at risk fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses	Placebo n=173 participants at risk Placebo IV or PO twice weekly for 6 weeks placebo: placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for 14 doses
Gastrointestinal disorders Necrotising Enterocolitis Neonatal	14.4% 27/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	16.2% 28/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Intestinal Perforation	6.4% 12/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	3.5% 6/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Meconium Ileus	1.1% 2/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Colonic Stenosis	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Ileal Perforation	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Intestinal Ischaemia	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Intestinal Obstruction	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Peritoneal Haemorrhage	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Pneumoperitoneum	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Rectal Prolapse	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Gastrointestinal disorders Small Intestinal Perforation	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Sepsis Neonatal	2.7% 5/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	6.9% 12/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Staphylococcal Sepsis	2.1% 4/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Osteomyelitis	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Arthritis Bacterial	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Candida Sepsis	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Candidiasis	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Group B Streptococcus Neonatal Sepsis	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Meningitis	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Infections and infestations Pneumonia Klebsiella	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Respiratory, thoracic and mediastinal disorders Neonatal Respiratory Failure	4.8% 9/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	1.2% 2/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Respiratory, thoracic and mediastinal disorders Neonatal Respiratory Arrest	1.6% 3/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Respiratory, thoracic and mediastinal disorders Neonatal Respiratory Distress Syndrome	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	1.2% 2/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Respiratory, thoracic and mediastinal disorders Pneumothorax	1.1% 2/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Respiratory, thoracic and mediastinal disorders Bronchopleural Fistula	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Respiratory, thoracic and mediastinal disorders Pleural Effusion	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Respiratory, thoracic and mediastinal disorders Pulmonary Haemorrhage	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Nervous system disorders Intraventricular Haemorrhage Neonatal	1.1% 2/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	1.7% 3/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Nervous system disorders Hydrocephalus	1.1% 2/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Nervous system disorders Convulsion Neonatal	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Nervous system disorders Cerebral Ventricle Dilatation	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Cardiac disorders Bradycardia Neonatal	1.1% 2/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Cardiac disorders Neonatal Cardiac Failure	1.1% 2/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Cardiac disorders Cardio-Respiratory Arrest	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Cardiac disorders Cardio-Respiratory Arrest Neonatal	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Vascular disorders Neonatal Hypotension	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	1.7% 3/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Vascular disorders Deep Vein Thrombosis	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Vascular disorders Vena Cava Thrombosis	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Vascular disorders Venous Thrombosis Limb	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
General disorders Neonatal Multi-Organ Failure	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	1.7% 3/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
General disorders Infusion Site Extravasation	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Renal and urinary disorders Renal Failure	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Renal and urinary disorders Renal Failure Neonatal	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Renal and urinary disorders Renal Failure Acute	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Congenital, familial and genetic disorders Patent Ductus Arteriosus	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Congenital, familial and genetic disorders Ileal Atresia	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Blood and lymphatic system disorders Thrombocytopenia	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Endocrine disorders Adrenal Insufficiency	1.1% 2/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Injury, poisoning and procedural complications Endotracheal Intubation Complication	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Injury, poisoning and procedural complications Gastrointestinal Stoma Complication	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Investigations Bilirubin Conjugated Increased	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Investigations Oxygen Saturation Decreased	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Eye disorders Retinopathy of Prematurity	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Musculoskeletal and connective tissue disorders Soft Tissue Necrosis	0.53% 1/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.00% 0/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks
Skin and subcutaneous tissue disorders Skin Necrosis	0.00% 0/188 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks	0.58% 1/173 • From time of first dose of study drug until 30 days following the last dose, up to approximately 10 weeks